Tuesday, April 29, 2014

How well can computers interact with humans? Certainly computers play a mean game of chess, which requires strategy and logic, and "Jeopardy!," in which they must process language to understand the clues read by Alex Trebek (and buzz in with the correct question).

But in recent years, scientists have striven for an even more complex goal: programming computers to read human facial expressions.

We all know what it's like to experience pain that makes our faces twist into a grimace. But can you tell if someone else's face of pain is real or feigned?

The practical applications could be profound. Computers could supplement or even replace lie detectors. They could be installed at border crossings and airport security checks. They could serve as diagnostic aids for doctors.

Researchers at the University of California, San Diego, have written software that not only detected whether a person's face revealed genuine or faked pain, but did so far more accurately than human observers.

While other scientists have already refined a computer's ability to identify nuances of smiles and grimaces, this may be the first time a computer has triumphed over humans at reading their own species.

"A particular success like this has been elusive," said Matthew A. Turk, a professor of computer science at the University of California, Santa Barbara. "It's one of several recent examples of how the field is now producing useful technologies rather than research that only stays in the lab. We're affecting the real world."

People generally excel at using nonverbal cues, including facial expressions, to deceive others (hence the poker face). They are good at mimicking pain, instinctively knowing how to contort their features to convey physical discomfort.

And other people, studies show, typically do poorly at detecting those deceptions.

In a new study, in Current Biology, by researchers at San Diego, the University of Toronto and the State University of New York at Buffalo, humans and a computer were shown videos of people in real pain or pretending. The computer differentiated suffering from faking with greater accuracy by tracking subtle muscle movement patterns in the subjects' faces.

"We have a fair amount of evidence to show that humans are paying attention to the wrong cues," said Marian S. Bartlett, a research professor at the Institute for Neural Computation at San Diego and the lead author of the study.

For the study, researchers used a standard protocol to produce pain, with individuals plunging an arm in ice water for a minute (the pain is immediate and genuine but neither harmful nor protracted). Researchers also asked the subjects to dip an arm in warm water for a moment and to fake an expression of pain.

Observers watched one-minute silent videos of those faces, trying to identify who was in pain and who was pretending. Only about half the answers were correct, a rate comparable to guessing.

Then researchers provided an hour of training to a new group of observers. They were shown videos, asked to guess who was really in pain, and told immediately whom they had identified correctly. Then the observers were shown more videos and again asked to judge. But the training made little difference: The rate of accuracy scarcely improved, to 55 percent.

Then a computer took on the challenge. Using a program that the San Diego researchers have named CERT, for computer expression recognition toolbox, it measured the presence, absence and frequency of 20 facial muscle movements in each of the 1,800 frames of one-minute videos. The computer assessed the same 50 videos that had been shown to the original, untrained human observers.

The computer learned to identify cues that were so small and swift that they eluded the human eye. Although the same muscles were often engaged by fakers and those in real pain, the computer could detect speed, smoothness and duration of the muscle contractions that pointed toward or away from deception. When the person was experiencing real pain, for instance, the length of time the mouth was open varied; when the person faked pain, the time the mouth opened was regular and consistent. Other combinations of muscle movements were the furrowing between eyebrows, the tightening of the orbital muscles around the eyes, and the deepening of the furrows on either side of the nose.

The computer's accuracy: about 85 percent.

Jeffrey Cohn, a University of Pittsburgh professor of psychology who also conducts research on computers and facial expressions, said the CERT study addressed "an important problem, medically and socially," referring to the difficulty of assessing patients who claim to be in pain. But he noted that the study's observers were university students, not pain specialists.

Dr. Bartlett said she didn't mean to imply that doctors or nurses do not perceive pain accurately. But "we shouldn't assume human perception is better than it is," she said. "There are signals in nonverbal behavior that our perceptual system may not detect or we don't attend to them."

Dr. Turk said that among the study's limitations were that all the faces had the same frontal view and lighting. "No one is wearing sunglasses or hasn't shaved for five days," he said.

Dr. Bartlett and Dr. Cohn are working on applying facial expression technology to health care. Dr. Bartlett is working with a San Diego hospital to refine a program that will detect pain intensity in children.

"Kids don't realize they can ask for pain medication, and the younger ones can't communicate," she said. A child could sit in front of a computer camera, she said, referring to a current project, and "the computer could sample the child's facial expression and get estimates of pain. The prognosis is better for the patient if the pain is managed well and early."

Dr. Cohn noted that his colleagues have been working with the University of Pittsburgh Medical Center's psychiatry department, focusing on severe depression. One project is for a computer to identify changing patterns in vocal sounds and facial expressionsthroughout a patient's therapy as an objective aid to the therapist.

"We have found that depression in the facial muscles serves the function of keeping others away, of signaling, 'Leave me alone,' " Dr. Cohn said. The tight-lipped smiles of the severely depressed, he said, were tinged with contempt or disgust, keeping others at bay.

"As they become less depressed, their faces show more sadness," he said. Those expressions reveal that the patient is implicitly asking for solace and help, he added. That is one way the computer can signal to the therapist that the patient is getting better.

Jeffrey Mogil's students suspected there was something fishy going on with their experiments. They were injecting an irritant into the feet of mice to test their pain response, but the rodents didn't seem to feel anything. "We thought there was something wrong with the injection," says Mogil, a neuroscientist at McGill University in Montreal, Canada. The real culprit was far more surprising: The mice that didn't feel pain had been handled by male students. Mogil's group discovered that this gender distinction alone was enough to throw off their whole experiment—and likely influences the work of other researchers as well.

"This is very important work with wide-ranging implications," says M. Catherine Bushnell, a neuroscientist and the scientific director of the Division of Intramural Research at the National Center for Complementary and Alternative Medicine (NCCAM) in Bethesda, Maryland, who was not involved in the study. "Many people doing research have never thought of this."

Mogil has studied pain for 25 years. He's long suspected that lab animals respond differently to the sensation when researchers are present. In 2007, his lab observed that mice spend less time licking a painful injection—a sign that they're hurting—when a person is nearby, even if that "person" is a cardboard cutout of Paris Hilton. Other scientists began to wonder if their own data were biased by the same effect. "There were whisperings at meetings that this was confounding research results," Mogil says.

So he decided to take a closer look. In the new study, Mogil told the researchers in his lab to inject an inflammatory agent into the foot of a rat or mouse and then take a seat nearby and read a book. A video camera trained on the rodent's face assessed the animal's pain level, based on a 0- to 2-point "grimace scale" developed by the team. The results were mixed. Sometimes the animals showed pain when an experimenter was present, and sometimes they seemed just fine. So, on a hunch, Mogil and colleagues recrunched the data, this time controlling for whether a male or a female experimenter was present. "We were stunned by the results," he says. The rodents showed significantly fewer signs of pain (an average of a 36% lower score on the grimace scale) when a male researcher was in the room than when a female researcher—or no researcher at all—was there.

Thinking back to his Paris Hilton experiment, Mogil wondered whether the rodents were responding to the sight of a woman or man or to something more subtle. So he told the people in his lab to place their worn T-shirts near injected animals and then leave the room. Even when the humans weren't present, the results were the same. Rats and mice showed about a 36% lower score on the grimace scale when exposed to male versus female T-shirts, the team reports online today in Nature Methods. (Female mice were slightly more sensitive to the effect.) Placing a woman's T-shirt next to a man's T-shirt negated the impact. Bedding material from unfamiliar male mice and guinea pigs, as well as pet beds slept in by unsterilized male cats and dogs, produced the same response: Male odors seemed to act like painkillers.

Further testing showed that the rodents exposed to male odors were actually feeling less pain, rather than simply hiding the pain they were in. The male aroma ramped up their stress levels, which deadened the hurt. "It's really astounding that such a robust effect could have been missed for so many years," Mogil says.

He suspects the rodents are reacting to scent chemicals that male mammals have produced for eons. "It's a primordial response," he says. "If you smell a solitary male nearby, chances are he's hunting or defending his territory." If you're in pain, you're showing weakness.

Almost every animal behavior studied in the lab, from the effectiveness of experimental drugs to the ability of monkeys to do math, is affected by stress, notes Paul Flecknell, a veterinary anesthesiologist at Newcastle University in the United Kingdom who researches ways to alleviate pain in animals. "This could have an impact on just about everything."

Male odor could even influence human clinical trials. If a male doctor injects you with a new kind of pain medication, do you feel better because of the drug—or because of his gender? "It's not an unreasonable concern," Flecknell says.

The findings may also suggest why some labs have trouble reproducing the results of other groups. "Sometimes pharmaceutical companies can't replicate preclinical work," says Bushnell, who came to NCCAM to develop a pain research program. "This could help explain that."

Still, Mogil doesn't think scientists need to redo decades of animal research. "It's a confounding factor, but not a fatal one," he says. But going forward, he advises, researchers should pay more attention not to just what experiments they're doing, but also to who's doing the experiments. "I joke that the solution is to fire all the male researchers," Mogil says. "But at the very least, this is something teams should be noting in the methods sections of their papers. We can change the bath water without throwing out the baby."

Thursday, April 24, 2014

Exercise makes us tired. A new study helps to elucidate why and also suggests that while it is possible to push through fatigue to reach new levels of physical performance, it is not necessarily wise.

On the surface, exercise-related fatigue seems simple and easy to understand. We exert ourselves and, eventually, grow weary, with leaden, sore muscles, at which point most of us slow or stop exercising. Rarely, if ever, do we push on to the point of total physical collapse.

But scientists have long been puzzled about just how muscles know that they're about to run out of steam and need to convey that message to the brain, which has the job of actually telling the body that now would be a good time to drop off the pace and seek out a bench.

So, a few years ago, scientists at the University of Utah in Salt Lake City began studying nerve cells isolated from mouse muscle tissue. Other research had established that contracting muscles release a number of substances, including lactate, certain acids and adenosine triphosphate, or ATP, a chemical involved in the creation of energy. The levels of each of those substances were shown to rise substantially when muscles were working hard.

To determine whether and how these substances contributed to muscular fatigue, the Utah scientists began adding the substances one at a time to the isolated mouse nerve cells. Deflatingly, nothing happened when the scientists added the substances individually.

But when they exposed the cells to a combination of all three substances, many of the nerve cells responded. In living muscle tissue, these neurons presumably would send messages to the brain alerting it to growing muscular distress. Interestingly, the scientists found that different neurons responded differently, depending on how much of the combined substances the scientists added to the lab plates containing the mouse nerve cells.

Since rodent nerve cells are not people, however, the scientists next decided to repeat and expand the experiment in humans. For a study published in February in Experimental Physiology, they recruited the thumbs of 10 adult men and women. The entire volunteers showed up at the lab, but only their thumbs were needed, since the researchers wanted to study muscles that were accessible and easily held still. Those in the thumb served nicely.

So, asking each volunteer not to move his or her hand, the researchers injected lactate, ATP or the various acids just beneath the tissue covering one of the muscles in the thumb. After the discomfort from the injection had faded, they asked the volunteers if they felt anything. None did.

They then injected volunteers' thumbs with the three substances combined and at a level comparable to the amounts produced naturally during moderate exercise. After a few minutes, the volunteers began to report sensations similar to fatigue, describing their thumbs as feeling heavy, tired, puffy, swollen and, in one case, "effervescent," although the thumbs had not been exercised at all.

In a subsequent injection, the researchers increased the amount of the combined substances until they approximated those produced during strenuous exercise. The volunteers reported intensified sensations of muscular fatigue and also some glimmerings of aching and pain.

Finally, the researchers upped the levels of the substances until they were similar to what is seen during all-out, exhausting muscular contractions. After this injection, the volunteers reported considerable soreness in their thumbs, as if the muscles had been completing a grueling workout.

What the study's findings indicate, said Alan R. Light, a professor at the University of Utah and senior author of the study, is that the feeling of fatigue in our muscles during exercise "probably begins" when these substances start to build up. Small amounts of the combined substances stimulate specific nerve cells in the muscles that, through complicated interactions with the brain, cause the first feelings of tiredness and heaviness in our working muscles.

These feelings bear only a slight relationship to the remaining fuel and energy in our muscles. They don't indicate that the muscle is about to be forced to stop working. But they are an early physiological warning system, a way for the body to recognize that somewhere up ahead lies a limit.

Each subsequent increase in the levels of lactate and other substances amplifies the sense of fatigue, Dr. Light said, until the substances become so concentrated that they apparently activate a different set of neurons, related to feelings of pain. At that point, the exercise starts to hurt and most of us sensibly will quit, staving off muscle damage should we continue.

Of course, improvements in physical performance sometimes demand that we continue through fatigue and on to achiness. "There is some truth" to the adage about "no pain, no gain," Dr. Light said. But disregarding all the signals from your muscles can be misguided, he said.

In recent experiments at his lab, cyclists who were given mild opiates that block the flow of nerve messages from the muscles to the brain and vice versa could ride faster than they ever had before, with a sense of unfettered physical ease — until, without warning, their leg muscles buckled and, limp and nearly paralyzed, they had to be helped from their bikes. "Ignoring fatigue and pain is not a good, long-term competitive strategy," Dr. Light said.

Better, he said, to attend to the messages from your muscles and calibrate training accordingly. Should your exercise goal be to become faster or stronger, find a pace or intensity that allows you to work out near and occasionally just beyond the boundary between fatigue and pain, a line that will differ for each of us and vary day to day. If on the other hand, your goal, like mine, is easier, pleasurable and sustainable exercise, consider an intensity at which your muscles grow only slightly heavy and tired and, if we are fortunate, effervescent.

Sunday, April 13, 2014

Doctors are prescribing opioid painkillers to pregnant women in astonishing numbers, new research shows, despite the fact that risks to the developing fetus are largely unknown.

Of 1.1 million pregnant women enrolled in Medicaid nationally, nearly 23 percent filled an opioid prescription in 2007, up from 18.5 percent in 2000, according to a study published last week in Obstetrics and Gynecology, the largest to date of opioid prescriptions among pregnant women. Medicaidcovers the medical expenses for 45 percent of births in the United States.

The lead author, Rishi J. Desai, a research fellow at Brigham and Women's Hospital, said he had expected to "see some increase in trend, but not this magnitude."

"One in five women using opioids during pregnancy is definitely surprising," he said.

In February, a study of 500,000 privately insured women found that 14 percent were dispensed opioid painkillers at least once during pregnancy. From 2005 to 2011, the percentage of pregnant women prescribed opioids decreased slightly, but the figure exceeded 12 percent in any given year, according to Dr. Brian T. Bateman, an anesthesiologist at Massachusetts General Hospital, and his colleagues. Their research was published in Anesthesiology.

Dr. Joshua A. Copel, a professor of obstetrics, gynecology and reproductive sciences at Yale School of Medicine in New Haven, Conn., said he was taken aback by the findings, which come even as conscientious mothers-to-be increasingly view pregnancy as a time to skip caffeine, sushi and even cold cuts.

"To hear that there's such a high use of narcotics in pregnancy when I see so many women who worry about a cup of coffee seems incongruous," he said.

Tuesday, April 08, 2014

Leaders of a major effort to systematically classify all common chronic pain conditions expect to have the first stage completed by mid-July 2014. The Pain Taxonomy, a project of the ACTTION public-private partnership, and the American Pain Society is one of two independent initiatives launched last spring to fill a widely perceived need for an updated evidence-based approach to improve diagnosis, treatment, and research of chronic pain (seePRF related news story).

Key issues and decisions of the initial consensus meeting held in May 2013 are summed up in the March 2014 issue of The Journal of Pain. The paper also describes the organizing principles, structured framework, and working outline for the final product.

"We had a lot of discussion about how revolutionary to be," said Roger Fillingim, director of the University of Florida Pain Research and Intervention Center of Excellence in Gainesville, US, and co-chair of the taxonomy initiative. In the end, the group decided the field lacked sufficient ammunition in the form of evidence to completely overthrow the prevailing diagnostic approach based on body location, affected tissues, and associated disease states.

"There was a lot of interest from virtually all the workgroup members in moving more toward a mechanism-based system," Fillingim said. "But we all recognize that existing knowledge doesn't support it. We don't know enough about the mechanisms underlying pain conditions and symptoms to have that as the primary foundation of the taxonomy. Over the years, we hope [the Pain Taxonomy] will evolve such that the mechanistic aspects take higher priority than signs and symptoms."

As a result, the group made neurobiological and psychosocial mechanisms one of the five dimensions to consider in the diagnosis of all chronic pain conditions. The other four dimensions are: core diagnostic criteria, such as symptoms and diagnostic tests; common features, including the epidemiology of the disorder; common medical comorbidities; and neurobiological, psychosocial, and functional consequences, such as the impact on sleep quality, mood, and interference with daily activities.

"Ultimately, [it] represents a syndromal taxonomy that incorporates existing information regarding mechanism, while recognizing the importance of individual differences in clinical presentation," write the authors in the paper. "This approach is designed to produce a practically useful and evidence-based taxonomy that allows a person-centered approach to classification and clinical care."

The Pain Taxonomy idea arose within the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the U.S. Food and Drug Administration. The group paired up with the American Pain Society (APS) to develop the ACTTION-APS Pain Taxonomy (AAPT).

A parallel project is led by a task force of the International Association for the Study of Pain (IASP) co-chaired by a German team. They are working under the auspices of the World Health Organization (WHO) to generate the first chapter dedicated to pain for the next revision of the International Classification of Diseases (ICD). Some pain experts are volunteering for both projects, which keeps information flowing informally in both directions, Fillingim said.

The IASP task force has had several meetings, drafted a proposal for a classification system, and hopes to find an international consensus in a May 20 meeting in Frankfurt, co-chair Winfried Rief of the University of Marburg, Germany, told PRF by email. "A major goal is the development of a virtual chapter of pain diagnosis" for the ICD-11, Rief wrote. "At present, we have defined seven categories, such as cancer-related pain, neuropathic pain, or primary pain." Rief characterizes the IASP/WHO draft as "slightly different" from the AAPT outline.

In the AAPT scheme, chronic pain disorders are organized into five major categories, including peripheral and central nervous systems; musculoskeletal pain; orofacial and head pain; visceral, pelvic, and urogenital pain; and disease-associated pains not classified elsewhere (such as cancer or sickle cell disease). Most of the categories have subsections—for example, the musculoskeletal category is broken down into osteoarthritis, other arthritides, low back pain, myofascial and fibromyalgia, and other musculoskeletal pain. For headaches, the orofacial and head pain category will defer to the International Classification of Headache Disorders (ICHD-2), which is, Fillingim and co-authors wrote, "the gold standard for headache research, including clinical trials, which has led to the development of evidence-based treatments for several headache disorders."

In fact, while being designed for easy clinical use, diagnostic systems in pain and psychiatry started as research tools, and the group expects researchers to be the early adopters, Fillingim told PRF. "We have talked about that quite a bit in person at the meeting and by email and telephone in the intervening period to be clear in our own minds." In a key benefit, the taxonomy will identify gaps in the evidence for diagnostic symptoms and underlying mechanisms, highlighting avenues for future pain research, the authors wrote.

At the May meeting, workgroups were set up around the categories. A steering committee and a research committee work across all categories, Fillingim said. At this stage, all the workgroups have leaders. Many have a full roster and have conducted the initial conference calls and emails to establish an agenda. The workgroups are charged with deciding which conditions they are going to cover and conducting systematic reviews of the existing literature to find out what is known about the classification of particular systems, he said. The reviews will inform the diagnostic criteria in the five dimensions for each chronic pain condition. "We have excellent workgroup leaders and really good people committed to getting the job done," Fillingim said.

In mid-July, representatives from the workgroups will come together for a second meeting to report on progress in data collection for the reviews. They may begin discussing the design of clinical studies to validate the specificity and sensitivity of the new diagnostic criteria. The taxonomy will be published by subcategory as standalone papers on a staggered timeline as they are completed. The plan calls for eventually compiling them into one guide, Fillingim told PRF.

The initial criteria and classification schemes are meant to be living documents that can be updated as new information becomes available, but the updating mechanism has not been established. In fact, he said, the whole thing may need to be restructured in 10 to 20 years, when more knowledge has accumulated.

A more immediate unknown is the final form of the complete first edition. "The ultimate plan is to assemble it all in a unified document in an electronic form or an online system," Fillingim said, "but there haven't been any final decisions."

As the content-based papers begin coming out, he said, the group will be eager for feedback from the pain research and clinical community.

Carol Cruzan Morton covers science, health, and the environment, and is based near Boston, Massachusetts, US.